Organoids: what are they and how do they help regenerative medicine?
Research on stem cells and developmental biology has made it possible to grow small bits of tissue in the laboratory called organoids. Scientists have created organoids that closely resemble many organs, from the liver and kidneys to the brain. What do researchers learn from growing organoids? How do they help regenerative medicine?
Obtaining human tissue to study organ development and diseases can be difficult due to limited availability or ethical concerns. Organoids provide researchers with new alternatives and opportunities for advancing research.
Researchers can use organoids to study the complex arrangements and interactions of cells in three-dimensions, which is not possible with most other experimental models.
Organoids are already being used to study diseases, discover new drugs and learn how cells assemble into organs.
Researchers are exploring how to generate organoids for a wide variety of human tissues. Procedures for growing organoids are still in the early stages of development, and many tissues have yet to be successfully grown as organoids.
Key to the growth of organoids in laboratories is determining the necessary growth conditions, such as physical structures to grow on and external growth factors.
Organoids are being examined for their potential to supply healthy new cells and tissues to advance regenerative medicines.
Organoids made from patients' induced pluripotent stem cells (iPSCs) could allow personalised medicines, with the potential to pre-test medical treatments on organoids rather than directly on people.
Most organoids contain only a subset of all the cells in a real organ. Creating fully functional and stable tissues will require developing ways to integrate other cellular systems into organoids, such as the vascular system.
The process of trying to replicate diseases in organoids is not always straightforward, but will likely reveal important aspects of diseases not previously appreciated.
Although organoids offer many benefits and opportunities to researchers, they still have limitations and will not be able to completely replace other experimental systems.
Organoids are groups of cells grown in laboratories that have organised themselves into cellular structures similar to those found in different organs. The name “organoid” actually means, “organ-like”. In many cases, the cells and cell structures give organoids abilities that are similar to the organ they resemble. For example, brain organoids develop layers of actively signalling nerve cells (neurons) and even ‘brain regions’ that are similar to regions of the human brain. Currently organoids that researchers are making can closely resemble some aspects of organs, however they are certainly not the same as a fully mature organ. Intestine organoids have many cell structures that resemble parts of the intestinal lining, but these organoids are typically the size of a pea, nowhere as large or as complex as our intestinal track. Though they may be small or only have some similarities to full organs, researchers are learning great deals from organoids. Many researchers believe organoids are the ‘next generation’ of biological tools for research, drug discovery and medicine.
Stem cells are the starting point for growing organoids. Researchers use different types of stem cells depending upon what type of organoid they are trying to make. Researchers have used pluripotent stem cells, such as embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), as well as stem cells found in every person’s organs, called tissue stem cells or adult somatic stem cells (ASCs). Different stem cells have different abilities, limitations and requirements for growing. (Learn more about different stem cells.) To grow organoids, researchers provide stem cells with specific growing conditions, which may require precise nutrients, growth factors, signalling molecules and physical environments (such as protein material to grow on). Often procedures for growing organoids require adding components in a particular order and at specific times. The growing conditions promote the stem cells to multiply and change (‘differentiate’) into the many types of cells typical of the organ the organoids resemble. Furthermore, the cells that the stem cells make are able to organise themselves into cellular structures. For example, kidney organoids have cells that behave like typical kidney cells and are organised to form ‘tubules’ just like those found in kidneys. Really, the hardest part of making an organoid is figuring out the precise conditions that stimulate and promote the stem cells. (This is not a simple task. It should be noted that this often takes years of research to accomplish.) Once the conditions are provided to stem cells, the cells multiply, differentiate, make cell-based structures and ultimately form the organoids all on their own.
Researchers are creating and using organoids for several reasons. The process of trying to create organoids that are as similar as possible to real organs allows researchers to learn what external factors direct stem cells to make specific organs during growth and development. However, this is just the beginning. Once researchers demonstrate a close resemblance between an organoid and an organ, they can then use that organoid to study many other aspects of organ development, disease, cell signalling and more. In addition to external signals stem cells receive; researchers are studying the many internal signals, proteins and genes critical for the cells to create a whole organ. These factors are important when trying to understand how a mutation in a gene might lead to a genetic (inherited) disorder. For example, studying intestinal organoids created from six patients with an intestine disorder (multiple intestinal atresia) has lead to the discovery of a gene important for intestine formation. The study showed that all six patients carried mutations in a single gene, which caused their intestinal stem cells to be unable to make ‘healthy’ organoids in the lab. Furthermore, the researchers were able to determine what signalling pathway the mutated protein affects in stem cells. Organoids are also allowing researchers to study infectious diseases in ways that were previously not possible. Brain organoids have been used to study how the ZIKA virus affects brain development and causes microcephaly, which is not possible to study with human brain tissue for obvious ethical reasons. In other cases, organoids are offering opportunities to study infections by viruses, bacteria and parasites that are better than previous methods have permitted. Just one example of this is the study on the life cycle of the parasite cryptosporidium, which causes the diarrheal disease commonly called “Crypto”. Organoids are proving to be very helpful in discovering many different aspects of human development and disease.
Although there currently are organoids that resemble over a dozen different organs of the body, it must be remembered that the ability to create organoids is still relatively new. Researchers are still developing methods to create organoids for numerous other tissues and organs. This effort will take time. In parallel to the diversity of organoids, scientists are constantly trying to make all organoids more representative of what real organ tissue looks like. The more accurately organoids represent real organ tissues, the more accurate researchers’ data becomes.
Currently, lab-grown tissues and organs for medical transplantation are science fiction. However, organoids are thought to be the very first step in this direction. If lab-grown tissues are to be used for medicine, proving that they closely match (or better yet, exactly match) real organs is essential. Scientists point out that one of the major benefits of lab-grown tissue is that genetic tools can be used to alter cells and remove genetic mutations that caused a patient’s disease in the first place. Obviously, there are ethical issues about altering the genetic code, but it could provide individuals with long-lasting medical solutions. Researchers are currently examining the safety and reliability of transplanting organoid-generated tissue in animals. It will likely be years before this approach is attempted in humans and it will be many, many more years before whole fully-functional organs can be grown for transplantation.
Cancer research is another area where organoids are being used. Many types of cancer have cells that act like stem cells and researchers are using these cells to grow cancer organoids. Researchers are using cells from different cancer patients to grow organoids that develop tumors in the lab, such as prostate cancer. Being able to grow mini-tumours that model various cancers allows researchers to study tumour growth in detail. Researchers hope to learn about the genes, proteins and signalling pathways cancer cells use and find new way to stop cancers from growing or metastasising (spreading throughout the body). In a slightly different approach, researchers are also studying what gene mutations cause healthy organoids to get tumours. This different approach is also very helpful in identifying what genes and signalling pathways are important for cancers to grow. It can also suggest what genes are important for protecting organs from cancer and what might be malfunctioning in cancer patients.
One last area that researchers are using organoids is to speed up research in general. Most organoids are small, which allows researchers to easily grow many of them at a time. Combining this benefit with modern high-throughput screening technologies allows researchers to test and compare hundreds of samples at the same time. Since organoids can model healthy and diseased organs as well as cancers, these high-throughput studies could become a very powerful tool for researchers to rapidly test new drugs, medical treatments and more.
There are likely many other ways that organoids will impact research and medicine, some of which remain to be discovered.
The Ethics of Brain Organoids - interview with bio-ethicist Sarah Chan
Sanger Institute - Organoids: Cancer in 3D – a YouTube video on cancer organoids
ISSCR – Organoids: What is the Science and What are the Clinical Applications? – a YouTube video of a lecture on brain organoids
TEDx Talk – How We Are Growing Organs in the Lab? – a YouTube video by Dr Jim Wells
ASCB – What’s it all about? Organoids – an article on organoids by the American Society for Cell Biology
HSC – Organoids: A new window into disease, development and discovery – an article on organoids by Harvard Stem Cell Institute
Use and application of 3D-organoid technology – A short review of scientific literature that discusses organoids and their use in research and medicine